July 25, 2018 — After a string of failures in Alzheimer’s disease treatment, drug companies say they might have a medication that both clears toxic amyloid proteins from the brain and significantly slows the rate of a patient’s mental decline.
In early July, drugmakers Biogen and Eisai set the Alzheimer’s world abuzz with news that they had an experimental drug — BAN2401 — that had shown positive results in human patients. At the time, they put out a news release touting their results as a first, and promised to show the actual study data at an upcoming medical meeting.
On Wednesday, they finally released the results everyone was waiting to see, and they were greeted by muted enthusiasm at the 2018 Alzheimer’s Association International Conference in Chicago.
“There’s a lot of intrigue here. It’s very interesting, but I think there are also a lot of questions, still,” says Julie Schneider, MD, a neurologist who is associate director of the Rush University Alzheimer’s Disease Center in Chicago. She has no financial interest in the drug and gets no money from either of the companies involved in its development, she says.
The company showed that over 18 months on the highest dose of the drug — 10 mg per kilogram of body weight given twice a month by IV — patients with early Alzheimer’s disease had big reductions of beta amyloid in their brains. They had about 93% less beta amyloid, compared with people in the study taking a placebo, or dummy medication. Beta amyloid is a sticky protein that is the main component of amyloid deposits that build up in the brains of Alzheimer’s patients. It’s considered a signature, and a likely cause, of the disease.
BAN2401 is what’s known as a monoclonal antibody. It is particularly good at helping the body get rid of soluble amyloid beta protein pieces, which are thought to be particularly toxic.
There have been other monoclonal antibodies that have reduced beta amyloid in the brain, but they’ve shown little clinical effect.
‘Statistically Significant’ Changes
While their mental abilities continued to decline over the course of the study, the group on the highest dose of BAN2401 showed less disease progression than the placebo group on a range of cognitive tests.
The biggest relative reductions were seen on a test called the ADAS-cog, a set of 11 tasks that patients complete. The tasks measure deficits in memory, language, attention, and other mental abilities. It includes things like remembering words on a list, drawing figures, and following directions.
The 161 patients on the highest dose of the drug had about 47% less decline in their test scores, compared with 247 patients who were getting a placebo medication. That difference was statistically significant.
About 15% of patients on the highest dose of the drug had serious side effects, compared with 17% of patients on a placebo. The most common side effects related to treatment were reactions to the IV.
At the beginning of the study, patients had an average score on the ADAS-cog of 22. After 18 months, patients on the placebo saw their scores decline by about 6 points. Patients who were taking the highest dose of BAN2401 declined by about 4 points on this test, an absolute difference of about 2 points.
Would that be enough to make a difference in a person’s daily life?
“The short answer is we don’t know,” says David S. Knopman, MD, a neurologist at the Mayo Clinic in Rochester, MN, who was present when the data was presented to reporters.
Knopman compared the BAN2401 results to the clinical trials of donepezil (Aricept), another Alzheimer’s drug, where the difference seen between patients on the drug and patients on the placebo was about 2 points on the ADAS-cog over 6 months.
“If [BAN2401] is a disease-modifying drug, the hope is that this difference would magnify over time. That’s just a hope,” Knopman said. Disease-modifying drugs slow the progression and course of a disease. They don’t cure it.
Possible Next Steps
In addition to the positive results on the ADAS-cog test, scientists saw significantly less disease progression on another measure of mental decline, the ADCOMS test. ADCOMS isn’t a widely accepted way to measure cognitive abilities. Instead, it’s a yardstick that Eisai created by cobbling together parts of recognized cognitive tests. The company created the test, it said, in the hopes that it would be more sensitive to changes in patients’ abilities than currently available tests.
In the end, there were 247 patients in the placebo, 52 who got 2.5 milligrams per kilogram of body weight (mg/kg) twice monthly, 51 who got 5 mg/kg once a month, 92 who got 5 mg/kg twice monthly, 253 who got 10 mg/kg once a month, and 161 who got 10 mg/kg twice monthly.
Lynn Kramer, MD, the chief clinical officer of Eisai Pharmaceuticals, said the company would present the BAN2401 data to regulatory authorities like the FDA and discuss next steps. He did not commit to starting a phase 3 trial — considered one of the final steps before regulatory approval — of the drug.
“It’s encouraging to see some effect, but I think personally, a lot more work needs to be done,” Schneider said. “We need more data. We need more time.”